Systemic Treatment in Colorectal Cancer

Abstract:

Epidemiology Colorectal cancer is a frequent disease in Western countries and ranks as second after lung cancer in men and breast cancer in women with about 500,000 new cases in Europe and 150,000 in the US. The mortality of 40 50% is high; however, in recent years this has been steadily improving due to early detection and better treatment measures, in particular adjuvant chemotherapy. In advanced disease, the improved efficacy of systemic chemotherapy leads to a substantial long-term survival by means of neoadjuvant chemotherapy followed by radical resection of metastases in the liver and/or lung.

On-going pre-clinical and clinical research with drugs directed to multiple targets is using colorectal cancer as a paradigm for early investigation of new drugs in combination with classical chemotherapy and this will hopefully create further substantial improvement in cancer treatment in the near future.

This disease is diagnosed mostly in resectable stages; however, 35 40% of patients have clinically detectable metastatic disease at the time of first diagnosis. Owing to the relatively aggressive nature of colon cancer in a relevant fraction of patients, synchronous and metachronous metastases occur in 50% of cases, resulting in an overall mortality of 40 45%. In recent years the introduction of adjuvant chemotherapy with single agent 5 fluorouracil (5FU), and most recently 5FU/oxaliplatin, significantly improved the long-term survival and cure rate of patients with stage II and III disease (no lymph nodes involved and lymph node positive, respectively), leading to a substantially reduced mortality, at least in the US. However, a stage shift with increasingly early detection by effective screening programmes (e.g. Hemoccult blood testing and more importantly a screening-colonoscopy as part of a general early detection programme, will reduce the mortality of colorectal cancer in the future. Also, in advanced disease, the efficacy of combination chemotherapy including new targeted drugs has improved the median survival from 1-1.5 to 2-2.5 and even nearly three years in some recent phase II studies. Some of these new developments will be described in the following.

Advances in Adjuvant Treatment of Resectable Disease

Peri-operative Treatment of Colon Cancer For patients with high risk stage II and III, adjuvant chemotherapy with 5FU/oxaliplatin has become standard. Treatment should start within 5 6 weeks after surgery and should be given for six months. Combination chemotherapy is preferred over singleagent 5FU since the relapse rate is significantly improved by the addition of oxaliplatin with acceptable short and long-term toxicity. Since a relapse in this disease mostly means an incurable situation, this event should be avoided as much as possible and combination chemotherapy should be preferred for most patients, as well as for older patients. Patients with stage II disease lacking risk factors (e.g. obstruction, perforation, less than 12 lymph nodes resected, poor grading) also might benefit from adjuvant chemotherapy, at least single agent 5FU as shown in the British QUASAR trial. Despite these data, the decision for adjuvant treatment in stage II disease without high risk features can be decided on an individual basis.

Several prognostic factors have been investigated; however, currently none of them form the basis for individual selection of patients for specific adjuvant treatment modalities. These factors include loss of heterozygosis, chromosome 18q, microsatellite stability or instability, insulin-like growth factor-?- receptor type II, excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), etc. None of these markers should be currently used as argument for or against adjuvant chemotherapy outside clinical trials.